Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX [3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone] and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-mug/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for approximately 60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.

Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: a review and roadmap for research.

International programme on chemical safety

Publisher Summary This chapter discusses the role of glutathione (GSH) and glutathione s-transferases in metabolism of chemical carcinogens and other electrophilic agents. GSH is a tripeptide (I) that is present in nearly all living cells and is the most abundant sulfhydryl compound present in animal tissues, mainly in the cytosol. The chapter illustrates the wide range of electrophilic agents, including several known mutagens and carcinogens, which conjugate with GSH, a process usually catalyzed by the GSH S-transferases. This conjugation is probably a protective mechanism and is the initial stage in mercapturic acid biosynthesis for the elimination of foreign compounds from the body. GSH S-transferases provide protection not only by catalyzing the conjugation of a potential toxicant with GSH, but also by preferentially binding, even covalently, that toxicant. The reactive electrophiles that conjugate with GSH also bind to DNA, RNA, and protein and identification of GSH conjugates provide information on the nature of these biologically active intermediates or even their immediate precursors. Thus, the knowledge of the way in which mutagens and carcinogens are metabolized is essential to a better understanding of their mode of action and of the processes for their detoxication.

The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents.

Guidelines for Canadian Drinking Water Quality

Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.

Molecular mechanisms of alcohol-mediated carcinogenesis

In the framework of a series of experiments conducted to evaluate the carcinogenic effects of oxygenated gasoline additives, MTBE was analyzed in an oral lifetime carcinogenicity study using 8-week-old male and female Sprague-Dawley rats. These experiments were part of a large research project on gasoline carcinogenicity performed at the Bentivoglio (BT) Castle Cancer Research Center of the Ramazzini Foundation and of the Bologna Institute of Oncology, MTBE, dissolved in oil, was administered by stomach tube at the doses of 1000, 250, or 0 mg/kg b.w., once daily, four days weekly, for 104 weeks. The animals were maintained until natural death. The last animal died 166 weeks after the start of the experiment, i.e., at 174 weeks of age. Under the tested experimental conditions, MTBE was shown to cause an increase in Leydig interstitial cell tumors of the testes and a dose-related increase in lymphomas and leukemias in female rats.

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Methyl-tertiary-butyl ether (mtbe) - a gasoline additive - causes testicular and lympho- haematopoietic cancers in rats

Carcinogenicity bioassays of vinyl chloride: I. Research plan and early results☆

Vinyl chloride (VC) has been produced in many countries for more than 30 years. It is the constituent of polyvinyl chloride (PVC), which nowadays is the plastic industrial material most used and diffused in the world. Moreover, it is used as a copolymer in Saran and other plastics, as a chemical intermediate, as a solvent, and as a propellant; in the past, for a short period, it was also used as an anesthetic. VC is at present produced at a rate of near 12 million tons per year. The following population groups may be exposed to VC: (1) workers engaged in the production of PVC and of VC and in the use of VC for other industrial purposes; (2) workers manufacturing PVC; (3) residents in areas neighboring on factories producing PVC and VC; and to a much lesser extent (4) people using products containing VC, as some propellent sprays; ( 5 ) people having contact with resins made with VC and with materials containing these resins; and (6) populations consuming food contained in plastics made with VC. Bioassays on the long term effects of VC were not available until 1970. This situation reflects the limited consideration which has been, up to the present, given to experimental bioassays in predicting the oncogenic effects on man of environmental and occupational agents. In part this is due to industrial and economical interests, in part to deficiencies in technical-scientific facilities, to the dilettantism of many experimental workers, and to the inadequacy of many experiments performed in the past. What is now happening with vinyl chloride and the story of vinyl chloride carcinogenicity should bring about greater consideration of experimental bioassays and finally induce a new turn in the field of occupational and environmental carcinogenesis. In other words, experimental prediction on the pathogenetic potential of occupational and environmental agents before they are produced and released on a large scale into the human environment should preclude the need for later epidemiological evidence.

Carcinogenicity bioassays of vinyl chloride: current results

In 1976, a systematic and integrated project of long-term carcinogenicity bioassays began at the Bentivoglio Experimental Unit of the Bologna Institute of Oncology. The Bologna experiments proved for the first time that benzene is an experimental carcinogen. These experiments demonstrated that benzene is carcinogenic when administered by ingestion and by inhalation and that it cause tumors in the various tested animal models (Sprague-Dawley rats, Wistar rats, Swiss mice, and RF/J mice). They also showed that benzene is a multipotential carcinogen, as it produces a variety of neoplasias in one or more of the tested animal models, including Zymbal gland carcinomas, carcinomas of the oral cavity, nasal cavities, skin, forestomach, and mammary glands, as well as angiosarcomas of the liver, hemolymphoreticular neoplasias, tumors of the lung, and possibly hepatomas. The Bologna experiments also indicated a clear-cut dose-response relationship in benzene carcinogenesis. This report presents the up-to-date results of the Bologna project. The need for more experimental research aimed at assessing the carcinogenic effects of low doses of benzene, of chemical mixtures containing benzene, and of benzene substitutes is emphasized. Also recommended are more comprehensive epidemiological investigations, extended to all types of malignancies, with particular regard to lung carcinomas.

Benzene, an experimental multipotential carcinogen: results of the long-term bioassays performed at the Bologna Institute of Oncology.

Until recently, the incidence of benzene carcinogenicity was based only on the association between benzene occupational exposure and human leukemia, with many limited case reports and scanty epidemiological data. Available experimental studies up to 1976 on animals were rare, fragmentary, and inadequate, and had failed to prove the carcinogenic effects of benzenes. However, an integrated project of long-term carcinogenicity bioassays, begun in our laboratory in 1976 and still continuing, has shown that benzene produces a variety of tumors in rats including Zymbal gland carcinomas, carcinomas of the oral cavity, hepatocarcinomas, and possibly mammary carcinomas, lymphoreticular neoplasias, and other malignancies. Some of the tumors caused by benzene are uncommon or unusual in the breed of rats studied. Therefore benzene must be considered, under the studied experimental conditions, a strong multipotential carcinogen. The need for more experimental research is emphasized, particularly to assess the carcinogenic effects of low doses. Also recommended are more comprehensive epidemiological investigations, extended to all types of malignancies, and the application of adequate measures for primary prevention.

Cesare Maltoni

Papers

Methyl-tertiary-butyl ether (mtbe) - a gasoline additive - causes testicular and lympho- haematopoietic cancers in rats

Carcinogenicity bioassays of vinyl chloride: I. Research plan and early results☆

Carcinogenicity bioassays of vinyl chloride: current results

Benzene, an experimental multipotential carcinogen: results of the long-term bioassays performed at the Bologna Institute of Oncology.

Benzene: A multipotential carcinogen. Results of long-term bioassays performed at the bologna institute of oncology